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TRPA1 Contributes to FGFR2c Signaling and to Its Oncogenic Outcomes in Pancreatic Ductal Adenocarcinoma-Derived Cell

Vanessa Mancini1, Salvatore Raffa1, Alessandra Fiorio Pla2

  • 1Department of Clinical and Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy.

Cancers
|February 10, 2024
PubMed

Insights

Transient receptor potential channel A1 (TRPA1) downregulation impacts pancreatic cancer cell invasion. TRPA1 contributes to Fibroblast growth factor receptor 2c (FGFR2c) signaling, suggesting it as a potential therapeutic target in pancreatic ductal adenocarcinoma.

Area of Science:

  • Molecular Oncology
  • Cell Signaling
  • Cancer Biology

Background:

  • Fibroblast growth factor receptor (FGFR) signaling is dysregulated in cancer.
  • FGFR2c variant and Protein Kinase C epsilon (PKCε) signaling promote epithelial-mesenchymal transition (EMT) and invasion in pancreatic ductal adenocarcinoma (PDAC).
  • Membrane proteins, such as transient receptor potential channels (TRPs), can modulate receptor tyrosine kinase signaling.

Purpose of the Study:

  • To investigate the role of TRPs in the FGFR2c/PKCε oncogenic axis in PDAC.
  • To determine TRPA1's contribution to FGFR2c-mediated signaling, EMT, and cell invasion.

Main Methods:

  • RNA interference (shRNA and siRNA) to modulate FGFR2c/PKCε axis and TRPA1 expression.
  • Ligand stimulation to activate FGFR2c signaling.
  • Biochemical assays, immunofluorescence, and in vitro cell motility assays.
  • Pharmacological inhibition using a selective TRPA1 channel antagonist.

Main Results:

  • FGFR2c/PKCε axis modulation (inhibition or activation) led to TRPA1 downregulation, indicating receptor-channel dependence.
  • TRPA1 depletion attenuated FGFR2c downstream signaling and reduced EMT.
  • TRPA1 contributes to FGFR2c-induced enhancement of PDAC cell invasiveness via MCL1/SRC signaling.
  • TRPA1's role in FGFR2c oncogenic potential is independent of its ion channel pore function.

Conclusions:

  • TRPA1 is a key mediator in the FGFR2c/PKCε oncogenic pathway in PDAC.
  • TRPA1 influences FGFR2c-driven EMT and cell invasion.
  • TRPA1 represents a potential therapeutic target for pancreatic ductal adenocarcinoma.
Keywords:
EMTFGFR2PDACPKCεTRPA1

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